The current treatment paradigm for acute myeloid leukemia (AML) is remission induction chemotherapy, followed by either consolidation chemotherapy or allogeneic stem cell transplantation (Mayer R J, Davis R B, Schiffer C A, Berg D T, Powell B L, Schulman P, Omura G A, Moore J O, McIntyre O R, Frei E, 3rd: Intensive postremission chemotherapy in adults with acute myeloid leukemia. Cancer and Leukemia Group B. The New England journal of medicine 1994, 331(14):896-903; Burnett A K: Treatment of acute myeloid leukemia: are we making progress? Hematology/the Education Program of the American Society of Hematology American Society of Hematology Education Program 2012, 2012:1-6; Klimek V M: Recent advances in the management of therapy-related myelodysplastic syndromes and acute myeloid leukemia. Current opinion in hematology 2013, 20(2):137-143; Stone R M: Consolidation chemotherapy for adults with AML in first remission: is there a best choice? Journal of clinical oncology: official journal of the American Society of Clinical Oncology 2013, 31(17):2067-2069.). As most patients diagnosed with AML are in their sixth or seventh decade of life, many are not candidates for standard remission induction chemotherapy because of the adverse toxicities, such as profound myelosuppression, life-threatening infections, and cardiotoxicity (Martner A, Thoren F B, Aurelius J, Hellstrand K: Immunotherapeutic strategies for relapse control in acute myeloid leukemia. Blood reviews 2013, 27(5):209-216; Peloquin G L, Chen Y B, Fathi A T: The evolving landscape in the therapy of acute myeloid leukemia. Protein & cell 2013, 4(10):735-746; Nazha A, Ravandi F: Acute myeloid leukemia in the elderly: do we know who should be treated and how? Leukemia & lymphoma 2014, 55(5):979-987; Ferrara F: Conventional chemotherapy or hypomethylating agents for older patients with acute myeloid leukemia? Hematological oncology 2014, 32(1):1-9). The development of new effective and safe treatments for AML is therefore needed. The “ideal” therapy should specifically target AML tumor cells with no side-effect on normal cells (Snauwaert S, Vandekerckhove B, Kerre T: Can immunotherapy specifically target acute myeloid leukemic stem cells? Oncoimmunology 2013, 2(2):e22943; Sweet K, Lancet J E: Novel therapeutics in acute myeloid leukemia. Current hematologic malignancy reports 2014, 9(2):109-117; Li K, Lv X X, Hua F, Lin H, Sun W, Cao W B, Fu X M, Xie J, Yu J J, Li Z et al: Targeting acute myeloid leukemia with a proapoptotic peptide conjugated to a Toll-like receptor 2-mediated cell-penetrating peptide. International journal of cancer Journal international du cancer 2014, 134(3):692-702; Konig H, Levis M: Is targeted therapy feasible in acute myelogenous leukemia? Current hematologic malignancy reports 2014, 9(2):118-127; Walter R B: The role of CD33 as therapeutic target in acute myeloid leukemia. Expert opinion on therapeutic targets 2014, 18(7):715-718). Since CD117 (c-Kit) is a transmembrane receptor on tumor cells surface and expresses on myeloid leukemia cells in 64% of patients with de novo AML and 95% of those with relapsed AML (Hans C P, Finn W G, Singleton T P, Schnitzer B, Ross C W: Usefulness of anti-CD117 in the flow cytometric analysis of acute leukemia. American journal of clinical pathology 2002, 117(2):301-305). Furthermore, CD117-expressing AML patients survived significantly shorter than CD117-negative patients and CD117 receptor high expressed at low complete remission rate (Doepfner K T, Boller D, Arcaro A: Targeting receptor tyrosine kinase signaling in acute myeloid leukemia. Critical reviews in oncology/hematology 2007, 63(3):215-230; Stirewalt D L, Meshinchi S: Receptor tyrosine kinase alterations in AML—biology and therapy. Cancer treatment and research 2010, 145:85-108; Marcucci G, Haferlach T, Dohner H: Molecular genetics of adult acute myeloid leukemia: prognostic and therapeutic implications. Journal of Clinical Oncology: 2011, 29(5):475-486; Ashman L K, Griffith R: Therapeutic targeting of c-KIT in cancer. Expert opinion on investigational drugs 2013, 22(1):103-115; Liang J, Wu Y L, Chen B J, Zhang W, Tanaka Y, Sugiyama H: The C-kit receptor-mediated signal transduction and tumor-related diseases. International journal of biological sciences 2013, 9(5):435-443, indicating that CD117 receptor represents a potential therapeutic target for AML).
Aptamers are synthetic single-stranded oligonucleotides (DNA or RNA), which have the ability to specifically bind to their targets with high affinity (Banerjee J, Nilsen-Hamilton M: Aptamers: multifunctional molecules for biomedical research. Journal of molecular medicine 2013, 91(12):1333-1342). As a “chemical antibody”, aptamers can be chemically synthesized, easily conjugated with therapeutic drugs, and more importantly, less or not immunogenic (Kanwar J R, Shankaranarayanan J S, Gurudevan S, Kanwar R K: Aptamer-based therapeutics of the past, present and future: from the perspective of eye-related diseases. Drug discovery today 2014; Xing H, Hwang K, Li J, Torabi S F, Lu Y: DNA Aptamer Technology for Personalized Medicine. Current opinion in chemical engineering 2014, 4:79-87; Zhou J, Rossi J J: Cell-type-specific, Aptamer-functionalized Agents for Targeted Disease Therapy. Molecular therapy Nucleic acids 2014, 3:e169; Hong B, Zu Y: Detecting circulating tumor cells: current challenges and new trends. Theranostics 2013, 3(6):377-394; Li X, Zhao Q, Qiu L: Smart ligand: aptamer-mediated targeted delivery of chemotherapeutic drugs and siRNA for cancer therapy. Journal of controlled release: official journal of the Controlled Release Society 2013, 171(2):152-162). Similarly to protein antibodies, synthetic aptamers have been widely studied as specific ligands to target cell surface biomarkers (Li X, Zhao Q, Qiu L: Smart ligand: aptamer-mediated targeted delivery of chemotherapeutic drugs and siRNA for cancer therapy. Journal of controlled release: official journal of the Controlled Release Society 2013, 171(2):152-162; Barbas A S, Mi J, Clary B M, White R R: Aptamer applications for targeted cancer therapy. Future oncology 2010, 6(7):1117-1126; Lassalle H P, Marchal S, Guillemin F, Reinhard A, Bezdetnaya L: Aptamers as remarkable diagnostic and therapeutic agents in cancer treatment. Current drug metabolism 2012, 13(8):1130-1144; Pednekar P P, Jadhav K R, Kadam V J: Aptamer-dendrimer bioconjugate: a nanotool for therapeutics, diagnosis, and imaging. Expert opinion on drug delivery 2012, 9(10):1273-1288; Radom F, Jurek P M, Mazurek M P, Otlewski J, Jelen F: Aptamers: molecules of great potential. Biotechnology advances 2013, 31(8):1260-1274; Zhao N, Pei S N, Parekh P, Salazar E, Zu Y: Blocking interaction of viral gp120 and CD4-expressing T cells by single-stranded DNA aptamers. The international journal of biochemistry & cell biology 2014, 51:10-18) for tumor cell detection and targeted therapy (Zhao N, You J, Zeng Z, Li C, Zu Y: An ultra pH-sensitive and aptamer-equipped nanoscale drug-delivery system for selective killing of tumor cells. Small 2013, 9(20):3477-3484). Recent studies reveal that antibody-drug conjugates are of a new biotherapeutics for targeted cancer therapy (Junutula J R, Raab H, Clark S, Bhakta S, Leipold D D, Weir S, Chen Y, Simpson M, Tsai S P, Dennis M S et al: Site-specific conjugation of a cytotoxic drug to an antibody improves the therapeutic index. Nature biotechnology 2008, 26(8):925-932; Adem Y T, Schwarz K A, Duenas E, Patapoff T W, Galush W J, Esue O: Auristatin antibody drug conjugate physical instability and the role of drug payload. Bioconjugate chemistry 2014, 25(4):656-664; Fauvel B, Yasri A: Antibodies directed against receptor tyrosine kinases: Current and future strategies to fight cancer. mAbs 2014, 6(4):838-851; Sievers E L, Senter P D: Antibody-drug conjugates in cancer therapy. Annual review of medicine 2013, 64:15-29). Notably, in comparing to protein antibodies the synthetic aptamers are smaller in size, and thus exhibits higher tissue penetration efficiency and faster binding capacity to tumor cells (Zeng Z, Zhang P, Zhao N, Sheehan A M, Tung C H, Chang C C, Zu Y: Using oligonucleotide aptamer probes for immunostaining of formalin-fixed and paraffin-embedded tissues. Modern pathology: an official journal of the United States and Canadian Academy of Pathology, Inc 2010, 23(12):1553-1558; Shigdar S, Lin J, Yu Y, Pastuovic M, Wei M, Duan W: RNA aptamer against a cancer stem cell marker epithelial cell adhesion molecule. Cancer science 2011, 102(5):991-998). These advanced chemical and biological features indicate potential value of synthetic aptamers in biomedical studies and clinical applications.
What is needed in the art is ssDNA ligands that specifically target CD117 proteins and selectively bind to CD117-expressing cells.